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J. Biol. Chem., Vol. 281, Issue 40, 29455-29467, October 6, 2006

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Specific Amino Acids of the Glycosyltransferase LpsA Direct the Addition of Glucose or Galactose to the Terminal Inner Core Heptose of Haemophilus influenzae Lipopolysaccharide via Alternative Linkages^*

Mary E. Deadman¹², Susanna L. Lundström, Elke K. H. Schweda, E. Richard Moxon¹, and Derek W. Hood¹

From the Department of Paediatrics, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom and the Clinical Research Centre, Karolinska Institutet and University College of South Stockholm, NOVUM, S-141 86 Huddinge, Sweden

Lipopolysaccharide is the major glycolipid of the cell wall of the bacterium Haemophilus influenzae, a Gram-negative commensal and pathogen of humans. Lipopolysaccharide is both a virulence determinant and a target for host immune responses. Glycosyltransferases have high donor and acceptor substrate specificities that are generally limited to catalysis of one unique glycosidic linkage. The H. influenzae glycosyltransferase LpsA is responsible for the addition of a hexose to the distal heptose of the inner core of the lipopolysaccharide molecule and belongs to the glycosyltransferase family 25. The hexose added can be either glucose or galactose and linkage to the heptose can be either 1–2 or 1–3. Each H. influenzae strain uniquely produces only one of the four possible combinations of linked sugar in its lipopolysaccharide. We show that, in any given strain, a specific allelic variant of LpsA directs the anomeric linkage and the added hexose, glucose, or galactose. Site-directed mutagenesis of a single key amino acid at position 151 changed the hexose added in vivo from glucose to galactose or vice versa. By constructing chimeric lpsA gene sequences, it was shown that the 3' end of the gene directs the anomeric linkage (1–2 or 1–3) of the added hexose. The lpsA gene is the first known example where interstrain variation in lipopolysaccharide core structure is directed by the specific sequence of a genetic locus encoding enzymes directing one of four alternative possible sugar additions from the inner core.

Received for publication, May 22, 2006 , and in revised form, July 13, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by the United Kingdom Medical Research Council (Program Grant).

² To whom correspondence should be addressed: University of Oxford, Dept. of Paediatrics, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom. E-mail: mary.deadman{at}paediatrics.ox.ac.uk.

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This article has been cited by other articles:

				M. E. Deadman, P. Hermant, M. Engskog, K. Makepeace, E. R. Moxon, E. K. H. Schweda, and D. W. Hood Lex2B, a Phase-Variable Glycosyltransferase, Adds either a Glucose or a Galactose to Haemophilus influenzae Lipopolysaccharide Infect. Immun., June 1, 2009; 77(6): 2376 - 2384. [Abstract] [Full Text] [PDF]

				E. K.H. Schweda, B. Twelkmeyer, and Jianjun Li Invited review: Profiling structural elements of short-chain lipopolysaccharide of non-typeable Haemophilus influenzae Innate Immunity, August 1, 2008; 14(4): 199 - 211. [Abstract] [PDF]